With the development of modern civilization, the quality of life has been improved, and with the medical development, the human lifespan has increased. However, the occurrence of various diseases, such as brain diseases including Parkinson's disease, depression, schizophrenia, Alzheimer's disease, etc.; heart diseases due to stress and dietary change; and various cancers due to exposure of humans to toxic substances, is gradually increasing. Accordingly, there is a need to develop an imaging diagnostic method which can diagnose these diseases at an early stage.
While various imaging diagnostic methods have been commercialized, positron emission tomography (PET) can be readily applied to clinical practice. The positron emission tomography is used to image the distribution of radiopharmaceuticals in vivo and their biochemical changes by intravenously injecting an organic compound labeled with a positron-emitting radioisotope. Therefore, it is possible to quantitatively measure in vivo biochemical changes at a lesion site through the positron emission tomography, which makes it possible to measure the progression of disease and predict the degree of treatment [A. Agool, R. H. Slart, K. K. Thorp, A. W. Glaudemans, D. C. Cobben, L. B. Been, F. R. Burlage, P. H. Elsing a, R. A. Dierckx, E. Vellenga, J. L. Holter, Nucl. Med. Commun. 2011, 32, 14.; N. Aide, K. Kinross, C. Cullinane, P. Roselt, K. Waldeck. O, Neels, D. Dorow, G. McArthur, R. J. Hicks, J. Nucl. Med. 2011, 51, 1559.; A. Debucquoy, E. Devos, P. Vermaelen, W. Landuyt, S. De Weer, F. Van Den Heuvel, K. Haustermans, Int. J. Radiat. Biol. 2009, 85, 763].
Radioisotopes used in the positron emission tomography include fluoride ([18F]F), carbon ([15C]C), nitrogen ([13N]N), oxygen ([15O]O), gallium ([68Ga]Ga), etc., and it is reported that the [18F]fluoride is of similar size to hydrogen, forms a stable bond with a carbon atom of an organic compound, is easy to be produced, and has an appropriate half-life (110 minutes), and thus is very suitable for the positron emission tomography [Lasne, M. C.; Perrio, C.; Rouden, J.; Barre, L.; Roeda, D.; Dolle, F.; Crouzel, C. Contrast Agents II, Topics in Current Chemistry, Springer-Verlag, Berlin, 2002, 222, 201-258.; Bolton, R. J. Labelled Compd. Radiopharm. 2002, 45 485-528].
In general, an organofluoro-18 compound is produced by reacting an alkyl halide or alkyl sulfonate with a fluorine salt, followed by substitution of a fluoride, and the [18F]fluoride is mainly used as the fluorine salt.
In the above alkyl halide or alkyl sulfonate, the halide is selected from the group consisting of Cl, Br, and I other than F, the sulfonate is —SO3R12, and R12 is an alkyl group or aryl group. More specifically, the alkyl group is preferably a C1-C12 alkyl sulfonate or halo C1-C12 alkyl group, and examples thereof include methanesulfonate, ethanesulfonate, isopropanesulfonate, chloromethanesulfonate, trifluoromethanesulfonate, and chloroethanesulfonate. Moreover, the aryl group is preferably selected from the group consisting of a phenyl group, a C1-C4 alkyl phenyl group, a halo phenyl group, a C1-C4 alkoxy phenyl group, and a nitrophenyl group, and preferred examples thereof include methylphenylsulfonate, ethylphenylsulfonate, chlorophenylsulfonate, bromophenylsulfonate, methoxyphenylsulfonate, and nitrophenylsulfonyl.
In general, the [18F]fluoride may be produced by irradiating [18O]H2O with protons using a cyclotron that is a circular accelerator [M. R. Kilbourn, J. T. Hood, M. J. Welch, Int. J. Appl. Radiat. Isot. 1984, 35, 599.; G. K. Mulholland, R. D. Hichwa, M. R. Kilbourn, J. Moskwa, J. Label. Compd. Radiopharm. 1989, 26, 140]. Moreover, the [18F]fluoride is generally produced at a very low concentration in [18O]H2O solution, and the [18 O]H2O solution is very expensive in terms of price and thus is recycled [K.-I, Nishijima, Y. Kuge, E. Tsukamoto, K.-I. Seki, K. Ohkura, Y. Magata, A. Tanaka, K. Nagatsu, N. Tamaki. Appl. Radiat. Isot. 2002, 57, 43; D. Schoeller, Obes. Res. 1999, 7, 519.; SNM Newsline, J. Nucl. Med. 1991, 32, 15N].
In order to remove a small amount of metal impurities produced during the recycling of the [18O]H2O solution and during the production of [18F]fluoride and to use only the production of [18F]fluoride in a labeling reaction, a method of exchanging anions using a quaternary ammonium salt-supported polymer cartridge (Chromafix or QMA) is generally used [D. J. Schlyer, M. Bastos, A. P. Wolf, J. Nucl. Med. 1987, 28, 764.; S. A. Toorongian, G. K. Mulholland, D. M. Jewett, M. A. Bachelor, M. R. Kilbourn, Nucl. Med. Biol. 1990, 17, 273.; D. M. Jewett, S. A. Toorongian, G. K. Mulholland, G. L. Watkins, M. R. Kilbourn, Appl. Radiat. Isot. 1988, 39, 1109.; G. K. Mulholland, R. D. T. J. Mangner, D. M. Jewett, M. R. Kilbourn, J. Label. Compd. Radiopharm. 1989, 26, 378.; K. Ohsaki, Y. Endo, S. Yamazaki, M. Tomoi, R. Iwata, Appl. Radiat. Isot. 1998, 49, 373-378.].
In order to elute the trapped [18F]fluoride from the quaternary ammonium salt-supported polymer cartridge, an aqueous solution containing a metal salt such as K2CO3 or an ammonium salt such as TBAHCO3 is used, and at this time, side reactions such as alcohol or alkene formation occur due to the alkalinity of the salts used during the reaction, which reduces the labeling efficiency. Moreover, complex side products, which are produced during the isolation of the organofluoro-18 compound by HPLC, may cause low specific activity [S. M. Okarvi, Eur. J. Nucl. Med. 2001, 28, 929.; J. C. Walsh, K. M. Akhoon, N. Satyamurthy, J. R. Barrio, M. M. Phelps, S. S. Gambhir, T. Toyokuni, J. Label. Compds. Radiopharm. 1999, 42, 51.; L. Lang, W. C. Eckelman, Appl. Radiat. Isot. 1994, 45, 1155.; L. Lang, W. C. Eckelman, Appl. Radiat. Isot. 1997, 48, 169.].
As such, during the elution of the [18F]fluoride from the polymer cartridge, the type and concentration of a salt used in the labeling reaction of the [18F]fluoride affect the labeling efficiency of the [18F]fluoride. Accordingly, there is need to provide a method for eluting the [18F]fluoride using a low-concentration of base and preferably for controlling the concentration of the base. Conventionally, a method for producing radiopharmaceuticals by controlling the concentration of the base with the use of inert salts has been reported, but it was found that there was a significant change in the yield of radiopharmaceuticals due to the difference in manufacturers of used inert salts or the difference in manufacturing numbers of the same manufacturer, indicating that it was difficult to ensure a stable supply of radiopharmaceuticals for clinical use. Moreover, in the case of the addition of a small amount of salt directly to a reactor, it was found that there was a change in the concentration of the added salt due to deliquescence of the salt, resulting in a change in the yield [S. Suchiro, S Vallabhajosula, S. J. Goldsmith, D. J. Ballon. Appl. Radiat. Isot. 2007, 65, 1350.; B. S. Moon, J. H. Park, H. J. Lee, J. S. Kim, H. S. Kil, B. S. Lee, D. Y. Chi, B. C. Lee, Y. K. Kim, S. E. Kim. Appl. Radiat. Isot. 2010, 68, 2279-2284.; S. J. Lee, S. J. Oh, W. Y. Moon, M. S. Choi, J. S. Kim, D. Y. Chi, D. H. Moon, J. S. Ryu. Nucl. Med. Biol. 2011, 38, 593.].
Accordingly, the present inventors have made efforts to solve the above-describe problems and found that it was possible to obtain a stable [18F]fluoride labeling yield by preventing the concentration of a base from changing due to an inert salt used and it was also possible to stably obtain a [18F]fluoride-labeled compound at high purity and high yield by using a [18F]fluoride eluent with an adjusted pH to prevent a change in the yield due to a difference in the concentration of the base that was added in a small amount, thereby completing the present invention.